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Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.

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PubMed ID: 30522820

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Sgritta M, Dooling SW, Buffington SA, Momin EN, Francis MB, Britton RA, Costa-Mattioli M

Neuron. Jan 2019

COMMENT: This interesting article analyzes the capacity of Lactobacillus reuteri for reversing social deficits in Mouse Models of ASD (Autism Spectrum Disorder). The work shows that, surprisingly, the treatment with L. reuteri is able to rescue the impaired social behavior in genetic, environmental, and idiopathic mouse models of ASD.

Maternal High-Fat Diet (MHFD) induces social deficits in the offspring that has a reduction of L. reuteri in gut and that was the origin of the idea of this work:

Studies in animal models have shown that gut microbes can modulate central nervous system (CNS)-driven behaviors in a very powerful way. Recently, in mice, we showed that maternal high-fat diet (MHFD) induces social deficits and a change in the gut microbiota of offspring that is characterized by a reduction of the commensal bacterial species L. reuteri. Consistent with these data, HFD-induced obesity in adult mice also leads to a reduction in the levels of L. reuteri. More importantly, selective treatment with L. reuteri reverses the social deficits in MHFD offspring.

L. reuteri modulates social behavior within the social reward circuits via the oxytocinergic system and in a vagus nerve-dependent manner:

More specifically, integrating multiple approaches, such as genetics, metagenomics, targeted vagotomies, immunohistochemistry, electrophysiology, and behavior, we began to dissect how L. reuteri impacts brain function. At the cellular and molecular levels, we provide new causal evidence that L. reuteri modulates social behavior and related changes in synaptic function within the social reward circuits via the oxytocinergic system. Moreover, at the systems level, we found that L. reuteri modulates social behavior independent of other microbes in the gut, and in a vagus nerve-dependent manner. Collectively, our findings provide new mechanistic insight into the gut-brain-axis signaling by which L. reuteri influences central nervous system function and selective behaviors.

This work demonstrates in mouse the influence of L. reuteri in behavior but, to apply this findings to design new therapies for human neurological disorders, the authors consider that it is needed to fulfill some criteria:

First, it would be important that the bacterial strain(s) restores the behavioral deficits of interest (e.g., social deficits) in multiple models of a disease, demonstrating the robustness of the microbial intervention. Specifically, we have shown that L. reuteri rescues social deficits in several mouse models of ASD, including a genetic model, three environmental models, and an idiopathic model of ASD. Future experiments to assess whether L. reuteri is also effective in non-mouse models of ASD, such as rats) or even nonhuman primates, would provide an even stronger rationale for moving toward developing therapies for humans. For instance, studying the effect of L. reuteri in pigs would be revealing, since their GI tract is more similar to that of humans. However, to our knowledge, pig models with social deficits are not currently available

Second, it will be of great significance to determine whether the effect of the candidate microbe(s) is direct or indirect. ...Surprisingly, we found that L. reuteri alone is sufficient to reverse the social behavioral deficits in GF mice, demonstrating that its effect on social behavior does not depend on other members of the microbial community .

Third, there should be a minimal understanding of the mechanism through which the gut microbe of interest modulates behavior. In this regard, we found that the L. reuteri-mediated rescue of social behavior depends on oxytocinergic and dopaminergic reward systems.  Moreover, our new results identified the main communication channel between the gut and the brain through which L. reuteri improves social behaviors in mouse models of ASD. It has been previously shown that microbes could modulate anxiety and depression-related behaviors via the vagus nerve. 

Fourth, to corroborate the validity of the microbial-based therapy, the effect of the probiotic treatment on behavior should be reproduced by other laboratories. Indeed, consistent with our results, an independent study by Tabouy et al. (2018) has recently found that L. reuteri successfully corrects social deficits in Shank3B_/_ mice.

In addition L. reuteri strain has been used in infants and has received a certification of Generally Recognized as Safe (GRAS) for use in humans by the FDA. 

New therapies for social deficits of behavior based on Lactobacillus reuteri are very promising and open new ways of application that could acting via gut-microbiota-brain axis to modulate important processes.

Contributor

Raquel Tobes